Emulsions containing resins



Patented Nov 7, 1950 v 2,529,460 I EMULSIONS CONTAINING RESINS Herman J. Schneiderwirth, Jenkintown, Pa., assignor to Sharp & Dohme, Incorporated, Philadelphia, Pa., a corporation of Maryland No. Drawing. Original application April 30, 1949, Serial No. 90,785. Divided and this application August 10, 1950, Serial No. 178,755.

. Claims. 1 I

This invention relates to the preparation of thixotropic emulsions whereby there is stably, suspendably dispersed throughout a thixotropic el a water immiscible substance, such as a natural or synthetic resinor a resin-like material, to form a thixotropic emulsion, and to the resulting novel thixotropic emulsions. These emulsions are called thixotropic since on standing they have a rigid consistency and after shaking or stirring are converted to a fluid which is readily pourable in the form of a liquid, stable, homogeneous emulsion. The transformation from the rigid form to the liquid form is" reversible and can be carried on from one form to the other without limit.

The thixotropic emulsions of this invention have a wide field of application and are useful in a number of industrial arts as in colors, pigment and paints, paper and paper coating, cosmetics, iood, rubber, leather finishing, and many others.

They are also particularly useful in the pharmaceutical industry in compounding various.

types of pharmaceutical and therapeutic preparations. Accordingly, the invention especially includes' thixotropic emulsions in which the re- One phase is an aqueous dispersion of a waterinsoluble, alkaline earth metal salt (this phase hereinafter being referred to as the water-insoluble, alkaline earth mineral salt cake or merely as the mineral salt cake). The second phase comprises at least one water-immiscible or waterinsoluble substance such as a resin or a resinlike material. These two phases are combined and converted into a thixotropic emulsion by the addition of a citrate or by the addition of citric acid and an alkaline reacting substance which is capable of forming a water-soluble salt with citric acid.

The aqueous phase, the water-immiscible or water-insoluble phase, and the citrate are the three essential ingredients of the thixotropic emulsion. It is to be understood, of course, that a wide variety of other ingredients can be added to the thixotropic emulsions of the invention. Some of these other ingredients are added to the thixotropic emulsionto extend the pH range in which thixotropy can be manifested. These sub stances are referred to below as thixotropy pH range extenders. Other substances can be added 2 either to decrease the time required for the thixotropic emulsion to be converted from the free flowing sol state to the rigid gel state or to increase the conversion time from the sol to the rigid gel state. Still other substances can be added either to solubilize the resin or to increase the concentration of water-insoluble substances in the aqueous phase and so decrease the conversion time of the thixotropic emulsion. Also, other substances, such as medicines or pharmaceuticals, can be added to the thixotropic emulsions of the invention to prepare compositions containing these ingredients in higher concentrations than could be obtained by previously known methods, and to maintain these medicines and pharmaceuticals in a more stable condition over a longer period of time than prior art compositions containing them.

The various ingredients which can be added, as well as the functions performed by them in the thixotropic emulsions, will be described more fully in the following discussion of the essential ingredients of the thixotropic emulsion.

The aqueous phase of the thixotropic emulsion contains as a major constituent, a colloidally dispersible, water-insoluble, alkaline earth metal salt, or a mixture of more than one of such salts, which, for the therapeutic preparations, are those that would be non-toxic in the dosage administered by the selected route. This. aqueous dispersion of water-insoluble, alkaline earth metal salts can be prepared, for example, by reacting two separate solutions of water-soluble salts. The first of these solutions, referred to as Solution A, is an aqueous solution of a water-soluble sulphate, phosphate, carbonate, silicate or other compound, such as an aluminate,

molybdate, borate, chromate, malate or others so long as the anion of said water-soluble compound forms a water-insoluble. salt with the selected alkaline earth metal, or Solution A can consist of an aqueous mixture of salts, the anion or anions of which will react in an aqueous medium witha cation which is an alkaline earth metal to precipitate the corresponding waterinsoluble alkaline earth metal salt.

The second of the necessary solutions, referred to as Solution 3," for use in the preparation of the major constituent of the gel system of the invention is an aqueous solution of a watersoluble, alkaline earth metal salt or mixture of such salts, the anion, or anions of which form a water-soluble salt with the cation or cations of the selected salt or salts in the Solution A used in the particular preparation.

Any desired concentration of the respective solutes can be used in each of the solutions A and B, up to a saturated solution. The latter is gen-' (rally advantageous for practical purposes. In reacting Solution A with Solution B, it is someq times convenient, although not essential, to use equal volumes of each solution. According y, the concentration of the solute in one of the two solutions should be such that the-quantitative concentration of its cations is the stoichiometric equivalent of the concentration of the anions in the other solution.

The reaction between the two solutions, A and B, can be carried out at any convenient temperature, but preferably below the boiling point of the solutions. However, the lower the temperature in general, the smaller is the particle size of the resulting insoluble salt formed and the better is the resulting thixotropic activity. The results improve and are best as the temperature of the mixture is below room temperature and very best when nearer to 0.

Either solution can be added to the other, but the particle size of the precipitated insoluble salt is advantageously smaller when solution B is added to solution A. In either event, the advantageously smaller particle size or better colloidal dispersibility is obtained irrespective of the order in which the solutions are added to one another when there is used sufficient of solution B to permit a slight excess of the water-soluble alkaline earth metal salt to remain unreacted.

Whichever solution is added to the other, the

addition is advantageously carried out with agitation, e. g. shaking or stirring, preferably the latter, which should at least be suflicient to give adequate intimate mixing of the two solutions. When the addition of the one solution to the other is completed, the precipitated water-insoluble, alkaline earth salt is homogeneously and stably dispersed throughout substantially the en tire aqueous medium and very little sedimentation occurs on standing.

The second essential step in preparing these salts in a form suitable for use in the preparation of a thixotropic composition is the concentration of the precipitated, water-insoluble, alkaline earth salts, incidentally accompanied by partial removal of the electrolytes formed during the inter-reaction of the solutes of the two solutions A and B. This concentration can be accomplished by convenient means for removal of the aqueous solution of the resulting water-soluble salts from the insoluble precipitate, advantageously by first decanting any supernatant either with or without initially adding more water to the supernatant. The concentration is carried out (and incidentally the major portion of the soluble electrolytes are removed) by filtration,

either suction or press, and with or without washcontains dissolved sulfates. When the end product is to be administered parenterally, the filter cake can go without washing for then the retained electrolytes can help the thixotropic emulsions approach isotonicity. If the end product is to be taken orally, further removal of electro- V lytes may be desirable to avoid too salty taste or organic salts described above.

interference with absorption of added ingredients.

In many cases the concentration can be done by centrifugation instead of, or in addition to, filtration.

Then, dependent upon the concentration of water-insoluble, alkaline earth metal salts desired in the end product sought, the necessary further amount of water can be removed from the filter cake preferably by hydraulic pressure using suitable bags or other means for retaining the solids. In this way, moist, water-insoluble, alkaline earth metal salt cakes containing up to as much and even more than fifty per cent of total solids'have been obtained. The amount of total solids in the thus formed mineral cake can advantageously vary between from about fifteen per cent to about seventy per cent, the remainder, that is. eighty-five per cent to-thlrty per cent of the cake being water.

It is not always necessary, however, to precipitate the water-insoluble, alkaline earth metal salts from an aqueous solution in order to obtain the desirable size and shape of the particles needed for the formation of the thixotropic emuls ion under the experimental conditions described. Particles of a size and shape suitable for the preparation of thixotropic gels and emulsions can also be obtained by mechanical sub-division of the alkaline earth metal salt or the other in- Very small particle size, often below one micron, can be obtained by micronizing the water-insoluble substance used. However, the shape of the mechanically sub-divided particles, as well as their size, does influence the'thixotropic characteristic of the final preparation. Care must therefore be exercised in preparing the aqueous dispersion of water-insoluble, alkaline earth'metal salts by mechanical means, since it is not always possible to control the shape and size of the particles in a micronizing process. 1

Starting with a mineral cake prepared by any of the methods described above, or by any other suitable method for preparing water-insoluble alkaline earth salts of a size and shape capable of being used in the preparation of thixotropic compositions. the thixotropic emulsions of the --invention can be prepared by (1) adding the water-immiscible or water-insoluble substance such as a resin or gum,- a resin-like substance and the like to the mineral cake containing the water-insoluble alkaline earth metal salt or a mixture of more than one of such salts and then by means of a strong mixer forming a paste which may be an emulsion or an aqueous semi-solid gel. This mass is then converted into a thixotropic emulsion by the addition of the selected citrate. In a modified procedure (2) the mineral cake is first converted to a thixotropic gel by the addition of a citrate of an alkaline-reactin agent either by the formation of the citrate in situ or by its addition as the desired citrate or mixture of citrates. there is added one or more of a variety of waterimmiscible or water-insoluble substances such as a resin or gum, a resin-like substance, or any other similar water-insoluble or water-immiscible substance, thereby obtaining an emulsion exhibiting thixotropic characteristics, Another method (3) comprises mechanically sub-dividing the crystalline, water-insoluble alkaline earth salts, as by micronizing the salts to the particle size and shape desired and adding to these flnely To the thixotropic gel thus formed,

pulverized salts, in any sequence, the water-immiscible or water-insoluble substances and the citrate. It is, of course, to be understood that modifications can be made in any of the above methods, and that additional ingredients can -be incorporated in the mineral salt cake, or in the water-insoluble substance, or'added to the thixotropic emulsion after it has been prepared. so long as these additional ingredients do not deleteriously aifect the thixotropic character of the composition. The thixotropic emulsions obtained by any of the above methods are complex mixtures in which the alkaline earth metal salts and the citrate are responsible fo the thixotropy exhibited by the final preparation. The dry preparation made by method 3 above may be converted into a thixotropic emulsion by adding water to it.

The amount of water-insoluble, alkaline earth metal salt needed in these complex thixotropic emulsions varies considerably from composition to composition. In some cases the water-insoluble. alkaline earth metal salts represent only one-twentieth of the total weight of the final composition, in other cases quantitiesup to onehalf of the total weight of the thixotropic emulsion can be employed.

In addition to the water-insoluble alkaline earth metal salts, other salts and compounds of finely sub-divided inorganic solids such as waterinsoluble salts of aluminum, bismuth, copper,

iron, nickel, titanium, zinc, and many others can ,be added even in considerable quantity without destroying the thixotropic character of the composition, regardless of whether these are added when the mineral cake is prepared, or at any later stage in the preparation of the emulsion. These additional water-insoluble substances are preferably added in powdered form after they have been, for example, micronized to a particle size of about five microns. In some cases, the addition of these inorganic solids improves the thixotropic characteristic of the emulsion by shortening the time required for the thixotropic emulsion to be converted from a free flowing sol to a rigid gel, while, at the same time, increasing the therapeutic effectiveness of the thixotropic emulsion. The effectiveness of these inorganic salts'in adjusting the conversion time of the thixotropic emulsions depends, however, upon the shape and also the size of the added finely powdered salt.

The second essential ingredient, the water-immiscible or water-insoluble substance, used in the preparation of the thixotropic emulsions of this invention can be at least one of a wide variety of water-immiscible or water-insoluble natural or synthetic resins or resin-like substances. Examples of the suitable natural and synthetic res ins or resin-like substances are the oleo-resins, as benzoin; the gum resins, as myrrh; the synthetic resins as 'vinylite resins, phenol-formaldehyde resins, urea-formaldehyde resins, and many others.

The amount of these materials which can be incorporated into the gel can be, in some instances, unusually high, comprising up to. about forty per cent or the total weight of the composition. This finding was unexpected because it is known that when a water-immiscible or water-insoluble substance, such as a resin or the like, is added to prior art thixotropic gels, the thixotropy is entirely destroyed, and a simple, usually unstable emulsion is formed, or, alternately. an immiscible mixture results which separates into various phases.

In some cases, it may be desirable to first dissolvethe resin, gum or other water-insoluble substance in a suitable non-aqueous solvent, such as an organic solvent which is non-miscible with water, such as cyclic hydrocarbons of the henzene series as benzene, toluene, and the like, or chloroform, carbon tetrachloride, butyl acetate, or essential oils such as oilof eucalyptus, terpentine, Wintergreen and the like, or they can be first dissolved in an organic solvent which is misciillgle with water. such as alcohol, acetone and the l c.

It is to be understood, f course, that these non-aqueous liquids can be incorporated into a thixotropic aqueous mineral dispersion merely to add their inherent property, and that they can be added at any time during the preparation of the thixotropic emulsion, thereby produclng a composition in which the minerals are dispersed in a mixture of water and non-aqueous dispersing liquids sometimes. together with other substances as described below. A detailed description of the method used to prepare these compositions is given in the examples.

When a water-immiscible substance is to be incorporated in the thixotropic composition, it may be advantageous in some instances to use a small quantity of an emulsifying agent in order to prevent the agglomeration of the waterimmiscible substance when it is added to the aqueous phase, thereby forming undesirably large globules of the water-immiscible substance in the thixotropic composition. The "emulsifying agents can be added to the water-immiscible substance before the latter is added to the other ingredients, or the emulsifier can be added during any stage of the preparation of the'thixotropic compositions, since they do not interfere undesirably with the thixotropic character of the 'thixotropic emulsions of the invention.

Examples of emulsifying agents which may be used are natural colloids, such as gum acacia, gum tragacanth, lecithin, egg yolk and the like, or synthetic organic chemicals such as ethanol v and the propanolamines, alkyl-substituted-decanols and -undecanols and the like compounds.

The third of the essential ingredients in the thixotrcpic emulsions of the invention, which can be added initially to the alkaline earth metal salt, or after the water-immiscible substance is added to the preparation, is a citrate of an alka' line-reacting cationic radical capable of forming a water-soluble salt with citric acid. Such salts are formed with any of the alkali metals or with a nitrogen base, for example, ammonia, ammonia derivatives as the primary, secondary, and tertiary aliphatic amines, alkanol' amines,

and quaternary ammonium bases, and the like, that are soluble in water.

This citrate can be prepared in situ from citric acid and the alkaline-reacting agent necessary to form the indicated citrate, or it can be used in the form of the already prepared citrate. It can be used in some compositions at as little as a fraction of one per cent and in others up to infrequently as much as five per cent or more depending on the total solids of the colloidallydispersed alkaline earth metal salts and on the thixotropic characterlstics desired in the end product. In general, it can be said that the lower the total solids content of the composition, the less citrate, while the higher the total solids, the more citrate is required to produce the thixotropic characteristics desired in the end product.

The thixotropic characteristic thecompositions, however, is not necessarily dependent solely upon the citrate. If after the thixotropic emulsion is prepared it is found that the thixotropic characteristics of the composition are weak,"

thixotropy over a wider pH range. Any of the carbohydrates whether it be a monosaccharide or a polysaccharide, is suitable so long as it is watersoluble, for example, a monosaccharide such as a pentose, as xylose, ribose, or a hexose as glucose (dextrose), mannose, fructose (levulose), a hepthat is, the conversion from the fluid to the rigid state takes place only after the composition has been allowed to stand for an extended length of time, such as for several hours or days, the time interval can be shortened to any desired extent by the addition of a phytate. On the other hand, if the conversion time from the rigid to the fluid state is too short, the conversion time can be increased to any desired extent by the addition of the proper amount of a complex phosphate.

These two phenomena are more fully decribed of the compositions embraced bythe invention can be modified to a point where it is at a minimum, that is where the conversion time between the sol and gel states is only very slight, or to a maximum where the conversion time between these two states is very pronounced. If it is not convenient or desirable to adjust the conversion time by using more or lesseitrate, as described above,the conversion time can be adjusted, for example, by controlling the concentration of the precipitated, readily dispersible, water-insoluble alkaline earth metal salts employed, since the lower the concentration of these salts the longer the conversion time of the thixotropic composition. The conversion time can also be controlled by adjusting the hydrogen ion concentration. When, for example the hydrogen ion concentration approaches or becomes greater than about pH 4.5, that is if the composition is more acid than pH 4.5, theconversion time becomes very short. 'Likewise, as the hydrogen ion concentration becomes less than about pH 9.0 the conversion time becomes very short. If for some purpose, however, a highly acidic or highly basic thixotropic emulsion is needed having a substantially longer conversion time than normally possible under these acidic or basic conditions, a thixotropy pH range extender may be added which will materially increase the conversion time of the composition. While thixotropic emulsions of this invention havebeen prepared without limitation as to pH, best results are obtained when the pH of the mixture is maintained between about pH 4.5 and about 9.0. The acidity of the composition can be adjusted by adding the required amount of, for example, citric acid, or any other organic or'inorganic acid which will not destroy the thixotropy property of the composition. If an alkaline pH is desired, more of the basic ingredients of the thixotropic composition can be added, such as additional carbonates and the like, or o'zher basic materials which are compatible with the thixotropic character of the composition and with the purpose for which the thixotropic emulsion is to be used. When such a thixotropic emulsion is prepared having a more alkaline or acid reaction, a minor portion of a pH range extender which is a water-soluble agent selected from the water-soluble carbohydrates and the aliphat c polyhydroxy alcohols, particularly the hexitols is added to maintain optimum tose, as mannoheptose, or a disaccharide as lactose, maltose, sucrose. Of the water-soluble, aliphatic, polyhydric alcohols, especially suitable are those that are water-soluble and have as many hydroxy groups as there are carbon atoms in the aliphatic chain, particularly the hexitols, for example, sorbitol, mannitol, dulcitol.

The quantity of pH range extender needed varies directly with the degree of acidity or alkalinity of the composition, .the more acid or the more basic, the more pH range extender needs to be added. The quantity of pH range extender needed is usually between about five to twenty per cent based on the total weight of the composition. It is, of course, possible to add only a minor portion of the selected pH range extender in order to stabilize the thixotropic emulsion. The conversion time of the composition can then be adjusted by any one or more of the other means for controlling the time required for thesol to be converted to the rigid gel.

An advantageous method for adjusting the conversion time of a thixotropic emulsion consists in adding either a phytate or a complex phosphate to the prepared composition. This method is particularly useful when a l rge quantity of a thixotropic emulsion is bein prepared and it is impractical to attempt to control the characteristics of the end product by too precise measurement of the ingredients used. The quantity of phytate or phosphate to be added depends upon the characteristics of the thixotropic emulsion desired.

If it is desired to decrease the conversion time of a thixotropic emulsion so that a shorter time is required for it to change from a freely flowing thixotropic emulsion to a rigid gel, a small amount of a finely divided phytate is added. The quantity of phytate needed for a specific preparation in order to obtain the desired thixotropic characteristic varies from case to case, but is easily determined by taking small samples from the thixotropic emulsion and adding varying quantities of the selected phytate until the desired conversion time is obtained. The amount of phytate needed seldom exceeds two per cent and generally is below one per cent. Phytin, which is the calcium salt of hexahydroxy cyclohexane hexaphosphoric acid can be advantageously used for this purpose. It is present in abundance in plant and animal organism and, of course, is completely non-toxic and harmless when taken by mouth. Salts other than the calcium s:-lt of this compound also produce the same effect on the thixotropic emulsion. Such salts include iron or magnesium phytate as well as the various other salts, such as the barium,

copper, lead, lithium, manganese, silver,.sodium,

strontium and the like metal salts of phytic acid.

A thixotropic emulsion which exhibits too short a conversion time between the sol and the rigid gel can also be adjusted so that the conversion from one state to the other will take place at any longer period desired. The compounds used for this purpose are complex alkali metal salts of phosphoric acid, such as a complex alkali metal salt of an ortho-, meta-, or pyrophosphate. As examples of these salts there can be mentioned sodium tetraphosphate,sodium tripolyphosphate, sodium hexametaphosphate, tetrasodium pyrophosphate, sodium tetrametapyrophosphate, and the like. Polymers of metaphosphoric acid can also be used in like manner to increase the conversion time of the thixotropic emulsion.

The quantity of the complex phosphate needed to increase the conversion time of a thixotropic emulsion can be determined in the same manner as described above for the phytate. The amount of complex phosphate required is usually less than one per cent and is seldom as high as about two per cent.

These complex phosphates can also be used to adjust the conversion time of a thixotropic emulsion to.which, for instance, too much phytin has been added. In like manner, phytin can be added to a thixotropic emulsion to which too large a quantity of a complex phosphate was added in order to decrease the conversion time to any desired degree.

The use of phytin or any other metal salt of phytic acid to decrease the conversion time of a thixotropic emulsion, as well as the use of complex alkali metal phosphates to increase the conversion time of a thixotropic composition, has never been known or used before for this purpose, and it is considered a new and important feature of this invention.

For any desired specific purpose, there can be added to the thixotropic emulsions of the invention other ingredients compatible with the maintenance of its thixotropic characteristics. An advantageous feature of the thixotropic emulsion of this invention is the possibility of having these additional ingredients present in a higher concentration than is ordinarily available in compositions heretofore prepared, as well as in a remarkably stable form. Particularly for thera-- peutic compositions, there can be included, for example, ingredients for the treatment of metabolic deficiencies as any of the available vitamin or vitamin factors whether water-soluble, or oilsoluble, or any of the suitable amino acids, proteins, protein-hydrolysates and the like; or antibacterial agents compatible with the system as sulfanilamide and the non-toxic, active, sulfanilamide derivatives, and other sulfcnamides; antibiotics, whether water-soluble or not, as penicillin, tyrothricin, streptomycin and the like; hormones; antacid substances other than those already contained in the thixotropic emulsion; biologicals, as bacterial vaccines, toxoids, virus vaccines; and other therapeutic or pharmaceutical ingredients compatible with the thixotropic system. In most cases, the incorporation of unusually high concentrations of these additional pharmaceuticals into the thixotropic emulsion of the invention is accomplished by adsorption of these additional agents on the colloidally dispersed, water-insoluble, alkaline earth metal salt constituent of the system. The thixotropic emulsions of the invention thus permit administration of their individual ingredients in a concentration higher than hitherto known in other types of compositions.

The therapeutic emulsions prepared accordin". to this invention show remarkable stability, contain their various ingredients in unusually high concentrations. and permit increased absorption from the intestinal tract of the medicinal ingredients of the thixotropic emulsion when it is administered by the oral route. These compositions have pharmaceutical elegance in that they have a smooth, even, creamy feel and are strikingly free of the unpleasant sensation of grittiness.

As the number of such thixotropic emulsions which can be prepared by the methods referred to above is unlimited, the invention will be illustrated by, but not restricted to, the following examples, each. one of which will represent a particular type or group of such thixotropic emulsions. To facilitate a clearer presentation, only one type of alkaline earth mineral salt cake (described in Example I), is being used throughout in the preparation of the various thixotropic emulsions of Examples II through VII. A substantial number of such mineral salt cakes have een described in U. S. Patent No. 2,487,600 to which reference should be made for additional illustrations of suitable mineral cakes.

The following example describes the preparation of a water-insoluble, alkaline earth mineral salt cake:

Example I.334 grams of crystalline calcium chloride, U. S. P., and 1'7 grams of crystalline magnesium chloride were dissolved in four liters of tap water, filtered, and cooled to 5 C. In another container, 432 grams of crystalline disodium phosphate, U. S. P., and 65 grams of sodium carbonate monohydrate, U. S. P., were dissolved in four liters of hot tap water, filtered and cooled to 20 C. The calcium chloride-magnesium chloride solution was then added to the disodium phosphate-sodium carbonate solution in an even, steady flow, with continuous stirring. The reaction mixture was permitted to stand overnight, after which, a white loosely packed precipitate, consisting of mixed calcium and magnesium phosphates and carbonates, was obtained. The supernatant liquid was decanted, and the precipitated water-insoluble salts were washed with distilled water until a sample of the washing showed only a slight cloudiness upon the addition of silver nitrate solution. The washed precipitate was then removed to a Buchn'er funnel, and a suction applied long enough to suck out as much of the water as could be practically removed in that way. The filter cake was then placed in a pressure bag and additional water expressed from it in a hydraulic press until the total solids content of the mineral cake was circa twenty-eight per cent.

Example II.--200 grams of the mineral cake prepared by the method of Example I were mixed with 1.0 grams of citric acid powder and stirred to a paste while warming on a water bath to 55 C. A resin solution (obtained by adding 20 grams of vinylite resin to 50 cc. of toluene and 20 cc. of oil of eucalyptus and heating the mixture on a water bath until the resin completey dissolved) was slowly added to the paste with continuous stirring 'until a homogeneous semi-soft paste resulted. The water bath was removed and stirring continued until the mixture cooled to room temperature. 3.5 grams of sodium citrate were then added thereby forming a complex thixotropic emulsion. The latter was twice put through a homogenizer and thereafter even stronger thixotropic characteristics were exhibited by the emulsion. A sample of this homogenized product readily converted from the.

free flowing liquid state to a rigid gel within less than two minutes when tested in a test tube of one inch diameter. Microscopic examination revealed the resin dispersed in the form of fine globular particles, evenly dispersed throughout the thixotropic emulsion.

13 quality of the vitamins are greatly enhanced, since they are maintained in a state of complete rest, evenly dispersed throughout a rigid Table A Mineral Citric acid Resin mm Conversion cake; powder, Solvent time, Gm Grams Kind Grams Kind Grams minutes 200 None Phenoliormaldeh do 25 Dioxane, 100cc Sodium 5.0 25 200 3. Urea i'ormaldehy e l Pyridine, 60 cc Ammonium. 4.5

The following example illustrates a thixotropic emulsion containing a resin, a carbohydrate (as a pH range extender), and as an additional water-insoluble substance, colloidally dispersed suli'ur.

Example LIL-Step 1: 50 grams of colloidal suli'ur powder were wetted with 40 cc. oi distilled water. 10 grams of sorbitol powder and 100 grams of the mineral cake prepared as in Example I were added and the whole was well mixed until a smooth paste was obtained. This paste was then warmed to 55 0.

Step 2: 10 grams of benzoin, U. S. P., were dissolved in 20 cc. of alcohol, U. S. P. over a waterbath. Alter the benzoin went completely into solution, this liquid was added gradually to the paste obtained in step 1. The combined pastes were removed from the water-bath and the whole stirred until the mixture cooled to room temperature. To this emulsified paste, there was added a mixture consisting of 0.6 gram of citric acid powder, 4.5 grams of sodium citrate powder and 10 grams of sorbitol. A thixotropic emulsion oi excellent appearance and good thixotropic characteristics was formed having a conversion time from a ireely flowing sol into a rigid gel of approximately twenty-eight minutes when tested in a test tube of one inch diameter.

Other thixotropic emulsions prepared by the method of Example III wherein the colloidal sulfur was replaced by another finely sub-divided powder, such as titanium dioxide, bismuth subcarbonate, copper benzoate and the like, were prepared. Examples of such thixotropic emulsions are given in the following table:

gel which can readily be converted to a free flowing sol when it is desired to administer the medicament.

The following example illustrates the preparation of thixotripic emulsions containing vitamins as its therapeutic ingredient:

Emmple IV.Step 1: 800 grams of the waterinsoluble, alkaline earth mineral salt cake prepared in Example I were placed in a suitable mixing kettle and 4 grams of citric acid powder were added thereto with continuous stirring.

Step 2: In a separate container, 200 cc. 01 tolu balsam tincture, U. S. P. (which is a solution of 40 grams of tolu dissolved in suiiicient alcohol to bring the total volume to 200 cc.) were mixed with 1.2 grams of a vitamin concentrate containing 450,000 U. S. P. units oi. Vitamin A and 90,000 U. s. P. units of Vitamin D in each gram of concentrate. To this mixture there was then added 3.3 grams of alphavtocopherol (also known as Vitamin E).

'I'he vitamin-resin mixture prepared in step 2 was then slowly added in a. thin stream and with continuous stirring to the mineral cake mixture prepared in step 1. After all the vitamin-resin mixture had been added, a white paste was obtained in which the vitamin-resin mixture was so well dispersed it was invisible to the naked eye. 18 grams of sodium citrate were then added to the paste with constant stirring, thereby converting the entire mixture into a thixotropic emulsion. The thixotropic emulsion thus obtained may be used directly or it may be put through a homogenlzer to form an excellent, free flowing sol having a conversion time of approxi- Table B Mineral Agent replacing suriur pH range extender Resin cake, Solvent, cc. acid, Gm Compound Grams Compound Grams Compound Grams Grams 900 Zn carbonate Lactrose--. 25 Myrrh-.... 30 Ethanol 100.....- 2.0 200 Cu benzoate 40 MannitoL- i5 Damar..." 10 Ch1oroiorm30.. None mately twenty minutes when tested in a test tube of 1 inch diameter. Conversion Various other water-immiscible substances may ffi be used in place of the resin used in Example II, Kind Grams such as any of the water-immiscible or waterinsoluble resins described above. Likewise, inmgmi .5 3 g stead of using the particular vitamins of Example IV, other vitamins, such as any of the B As described above, the thixotropic emulsions of the invention are particularly well adapted to carry a large number of pharmaceutical or medicinal agents. They are particularly useful for the preparation of vitamin compositions, since it is known that vitamins readily deteriorate when they are incorporated in ordinary liquid preparations. When the vitamins are incorporated in a thixotropic emulsion, however, the keeping and then added to the mineral salt cake as described above, or the vitamin or pharmaceutical product can be added separately after the waterimmiscible substance has been added to the mineral salt cake. In either event, the subsequent addition of the citratewill produce thixotropy in the same way as described above.

The following example illustrates the use of phytin to decrease the conversion time of a thixotropic emulsion from a freely flowing sol to a rigid gel:

Example V.-600 grams of an aqueous bismuth sub-carbonate and hydroxide gel dispersion (also known as Milk of Bismuth, National Formulary VII) was filtered and compressed until it contained forty per cent of total solids. This bismuth cake was then added to 60 grams of the water-insoluble, alkaline earth metal salt cake prepared as in Example I, and then 1.2 grams of citric acid powder were added forming a semisoft paste. To this paste, 100 cc. of camphorated opium tincture, U. S. P. were added in a slow. thin stream while the whole was vigorously stirred. (The camphorated opium tincture is prepared by mixing an alcohol-water extract of opium with camphor, oil of anise and benzoic acid.) 3.2 grams of sodium citrate powder were then added to this rather thin pasty mixture, to convert it into thixotropic emulsion having rather weak thixotropic characteristics. sion time from the freely flowing sol to the rigid gel state took over twelve hours when a sampfe of this thixotropic emulsion was placed in a test tube of one inch diameter. This weak thixotropic emulsion was divided into two equal portions. 0.75 per cent of finely powdered phytin was added with stirring to one of the portion thereby forming a thixotropic emulsion of dis- .tinctly stronger character, having a conversion time of sixty minutes when tested in a test tube of one inch diameter.

The following example illustrates the use of a complex phosphate to increase the conversion time of a thixotropic emulsion:

Example VI.To the second portion of the weak thixotropic emulsion prepared in Example V there was added, with stirring, 1.5 per cent of phytin which produced a thixotropic emulsion having a conversion time of approximately thirty minutes. One per cent of sodium hexametaphosphate was intimately dispersed throughout this viscous thixotropic emulsion thereby recon-- verting it to a thixotropic emulsion having the desired thixotropic characteristics, and a conversion time of ninety minutes when tested in a test tube of one inch diameter.

While the various specific examples describe the use of certain particular water-insoluble, alkaline earth metal salts, certain particular citrates and certain particular resins in the respectlve steps in the preparation of the corresponding thixotropic emulsions, any of these various ingredients can be replaced by any other examples of these respective agents as hereinabove described. It is possible, for example, even to employ ferrous or even ferric sulfate as a solute in solution A, whenthe anions of the solutes in solution B will form a water-insoluble salt with iron. Copper salts can be similarly employed in correspondin fashion.

While the Examples II through VI have been prepared respectively with certain individual and specific resins, any desired suitable individual or combination of resins can be employed. Likewise any compatible added agent such as an or- The convcrganic solvent, additional water-insoluble ingredients, or a therapeutic agent can be employed by similar incorporation into any thixotropic emulsion prepared according to the invention. While the examples show the incorporation of thera-,

peutieally effective ingredients at certain specific stages of the preparation, it is possible to include the particular therapeutic ingredients or other added ingredients at other stages of the preparation.

Some of the thixotropic emulsions of the invention can also be carefully dried under vacuum preferably at a low temperature, for example, 30-40 C., or the desired ingredients can be initially, substantially dry and intimately mixed in the dry state. From the dried state the thixotropic composition can be restored by addition of the required amount of water; or from the dried state, the composition can be prepared in the form of pellets or tablets for use in that form. 1

To prepare such a product by using initially dry ingredients, the water-insoluble, alkaline earth metal salt (or other water-insoluble addition substance which can be used along with these salts as described above) should have a particle size of preferably about five microns. This particle size can advantageously be obtained by modern micronizing processes and equipment. The following example illustrates the preparation of such a dry product.

Example VII.-Step 1: grams of calcium phosphate dibasic, average particle size approximately five microns, were added with stirring to a mixture of 15 grams of magnesium phosphate dibasic, 10 grams of calcium carbonate, 10 grams of calcium phytate, 6.6 grams of water-soluble, peptonized, iron manganese (containing 12.5 per cent of iron and 3.5 per cent of manganese), and 15 grams of mannitol, each ingredient having previously been micronized to a particle size of approximately five microns.

Step 2: 0.9 gram of a vitamin A and D concentrate containing 450,000 U. S. P. units of vitamin A and 90,000 units of vitamin D per gram of concentrate were mixed with 0.4 gram of an antioxidant consisting of a. mixture of corn oil, lecithin, gallic acid ester and natural tocopherol. To this vitamin-antioxidant mixture there was then added 2 grams of finely powdered gum acacia. and the whole triturated in a mortar to form a smooth, substantially dry powder.

The mixture formed in step 2 was then intimately dispersed throughout the mineral salt mixture prepared in step 1, thereby forming a completely dry product. A 10 gram sample of this product was set aside for further testing. This sample will be referred to below as mixture A. 3.5 grams of sodium citrate were then intimately mixed with the remainder of the dry product. A 10 gram sample of this mixture (referred to below as Mixture B) also was set aside for further testing. The remainder of the powderv mixture was made up in tablet form, which tablets produced a, thixotropic composition when dispersed in a suitable quantity of water. 5 grams of Mixture A (half of the sample of the dry product taken before the addition of sodium citrate), and 5 grams of Mixture B (half of the sample taken after the addition of sodium citrate) were each separately thoroughly dispersed in 8 cc. of distilled water. Each sample was then transferred to a test tube of one-half inch diameter and six inches in length and allowed to stand overnight. The test tube containing Mixture B 18 dispersed in water had converted to a rigid gel, which became a free flowing sol upon shaking the test tube. This sol upon standing readily became a rigid gel again, demonstrating its desirable thixotropic characteristics. The test tube containing Mixture A had no thixotropic characteristics whatsoever, the insoluble ingredients which were originally suspended in the 8 cc. of water were entirely precipitated and a clear supernatant liquid was formed above the precipil tate.

The remaining five grams of each of Mixture A and Mixture B were separately suspended in 100 cc. of distilled water. The sample containing Mixture B remained for the most part dispersed throughout the water with only the coarser particles settling to the bottom of the container. The sample containing mixture A formed a complete precipitate with a clear supernatant liquid.

The difference exhibited by Mixtures A and B when added to water is of great significance. When, for example, a tablet prepared from Mixture B is administered orally, the ingredients will readily disperse in the gastro-intestinal fluids thereby facilitating the absorption of the line mineral particles and other therapeutic ingredients from the intestinal tract. A tablet prepared from Mixture A, however, would resist dispersion in the intestinal fluids and would be absorbed only sparingly from the intestines.

While the above examples illustrate dry compositions, which upon the addition of water are converted into thixotropic emulsions containing a vitamin concentrate, it is to be understood that one or more pharmaceutical or medicinal ingredients can be used along with the vitamin concentrate or in place of it to form similar compositions suitable for therapeutic use.

The thixotropic emulsions of the invention are stable and show no effect from exposure to sunlight and darkness and inconsequential efiect on changes in temperature above the freezing point and below the boiling point. For example, no syneresis (e. g., separation of clear liquid above the gel upon standing) is ordinarily observed at room temperature and at temperatures above the freezing point, and any syneresis at room temperature is usually of a negligible degree. Some slight syneresis occurs upon heating, for example, to from 37 to 50 C., but usually to clear liquid above the gel does not exceed three per cent of the total original volume of the gel. While the thixotropic emulsion of the invention can be kept below the freezing point for a short time, if such exposure is for several days or more, the thixotropy is often irreversibly destroyed.

This application is a division of my co-pending application Serial No. 90,785, filed April 30, 1949, which in turn is a contnuation-in-part of my then co-pending application Serial No. 621,382, filed October 9, 1945, now Patent No. 2,487,600, which application in turn was in part a continuation of the then co-pending application Serial No. 457,532, now abandoned, filed September 4, 1942.

While the above described invention has been illustrated with respect to certain specific embodlments of it, it is understood modifications, variations and substitutions can be made in them, and that the invention is limited solely by the scope of the appending claims.

I claim:

1. A thixotropic emulsion comprising an aqueous vehicle, at least one water-insoluble alkaline earth metal salt of the group consisting of phosphate, carbonate, sulfate and hydroxide, stably suspendably dispersed therein, a water-soluble nitrate of an alkaline base dissolved in said aquebus vehicle in an amount sufficient but not over five percent, to produce the thixotropic character of the system, said alkaline base being a member ofthe group consisting of the alkali metal bases and the nitrogen bases, and at least one substance selected from the group consisting of a water-insoluble resin in an amount up to about forty percent.

2. A thixotropic emulsion according ,to claim 1. in which a phytate is also present in an amount suilicient, up to about two percent, to decrease the conversion time from the free flowing state to the rigid gel state of the thixotropic emulsion.

3. A thixotropic emulsion according to claim 1, in which a water-soluble phosphate selected from the class consisting of ortho-, meta-, and pyrophosphates and their polymers is present in an amount suflicient, up to about two percent, to increase the conversion time from the free flowing state to the rigid gel state of the thixotropic emulsion.

4. A thixotropic emulsion comprising an aqueous vehicle, at least one water-insoluble alkaline earth metal salt of the group consisting of phosphate, carbonate, sulfate and hydroxide, stably suspendably dispersed therein, a water-soluble citrate ofan alkaline base dissolved in said aqueous vehicle in an amount suflicient but not over five percent, to produce thethixotropic character of the system, said alkaline base being a member of the group consisting of the alkali metal bases and the nitrogen bases, and a water-insoluble synthetic resin in an amount up to about forty percent.

5. A thixotropic emulsion comprising an aque- 40 ous vehicle, at least one water-insoluble alkaline earth metal salt of the group consisting of phosphate, carbonate, sulfate and hydroxide, stably suspendably dispersed therein, a water-soluble citrate of an alkaline base dissolved in said aqueous vehicle in an amount sufiicient but not over five per cent, to produce the thixotropic character of the system, said alkaline base being a member of the group consisting of the alkali metal bases and the nitrogen bases, and a waterinsoluble natural resin in an amount up to about forty percent.

HERMAN J. SCHNEIDERWIRTH.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS 

1. A THIXOTROPIC EMULSION COMPRISING AN AQUEOUS VEHICLE, AT LEAST ONE WATER-INSOLUBLE ALKALINE EARTH METAL SALT OF THE GROUP CONSISTING OF PHOSPHATE, CARBONATE, SULFATE AND HYDROXIDE, STABLY SUSPENDABLY DISPERSED THEREIN, A WATER-SOLUBLE CITRATE OF AN ALKALINE BASE DISSOLVED IN SAID AQUEOUS VEHICLE IN AN AMOUNT SUFFICIENT BUT NOT OVER FIVE PERCENT, TO PRODUCE THE THIXTROPIC CHARACTER OF THE SYSTEM, SAID ALKALINE BASE BEING A MEMBER OF THE GROUP CONSISTING OF THE ALKALI METAL BASES AND THE NITROGEN BASES, AND AT LEAST ONE SUBSTANCE SELECTED FROM THE GROUP CONSITING OF A WATER-SOLUBLE RESIN IN AN AMOUNT UP TO ABOUT FORTY PERCENT. 